Method of administering central nervous system active compounds

ABSTRACT

A method of stimulating the central nervous system and of enhancing behavior by administering an effective amount of a compound of the formula   AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF WHEREIN N IS 0, 1 OR 2, R is hydrogen or lower alkyl of up to four carbons, R1 is lower alkyl of up to four carbon atoms, and R and R1 together with the nitrogen atom to which they are bonded are piperidino, morpholino or pyrrolidino.

United States Patent 1191 Simon et a].

[22] Filed:

[54] METHOD OF ADMINISTERING CENTRAL NERVOUS SYSTEM ACTIVE COMPOUNDS [75] Inventors: Pierre Simon, Sevres, ;France;

Jack Bernstein, New Brunswick; John Krapcho, 865E88 both of NJ.

[73] Assignee; EQ R. Squibb & Sons, lnc., .New

f Ns i v Oct. 6, 1970 [211 App]. No; 78,569

2,803,582 8/1957 Cherney .::260/472 [451 Jan. 2, 1973 Priina fi ifiafiiri5 Starfieyi"Fiiedman I Attorney-Lawrence S. L'evinson, Merle J. Smith,

Donald J. Perrella and Burton Rodney [57] v ABSTRACT A method of stimulating the central nervous system and 'of enhancing behavior by administering an effective amount of a compound of the formula and pharmaceutically acceptable acid additions alts thereof wherein n is 0, l or 2, R is hydrogen or, lower alkyl of up to four carbons, R is lower alkyl of up to four carbon atoms, and R and R together with the nitrogen atom to which they are 7 bonded are piperidino, morpholino or pyrrolidino.

7 Claims, No Drawings METHOD OF ADMINISTERING CENTRAL NERVOUS SYSTEM ACTIVE COMPOUNDS BACKGROUND OF THE INVENTION Compounds which stimulate the central nervous system and which enhance behavior have been the subject of considerable research. Amphetamine, for example, has been suggested as such a compound but is objectionable in that its use is subject to abuse and, in geriatric cases, it has the undesired effect of reducing appetite.

OBJECTS OF THE INVENTION It is, accordingly, an object of the present invention to provide a method for stimulating the central nervous system and enhancing behavior without the side effects attributed :to amphetamine-type compounds. Another object is to provide a method for the administration of compounds which achieve the foregoing objects. A further object is to provide dosage levels and formulations for the administration of these compounds. These and other objects of the present invention will be apparent from the following description.

DETAILED DESCRIPTION It has now been found that the central nervous system is stimulated and behavior is enhanced by administering an effective amount of a compound of the general formula and pharmaceutically acceptable acid addition salts thereof wherein n is 0, I or 2, R is hydrogen or lower alkyl of up to four carbon atoms, R is lower alkyl of up to four carbon atoms, and R and R, together with the nitrogen atomto which they are bonded are piperidino, morpholino or pyrrolidino.

Examples of typical lower alkyl-substituted amine compounds wherein the cycloalkyl ring may be cyclopentyl, cyclohexylor'cycloheptyl are as follows:

2-(mono-lower alkylaminomethyl)cycloalkyl paminobenzoate, e.g., 2- monomethylaminomethyl)cycloalkyl paminobenzoate, and 2-(di-lower alkylaminomethyl)cycloalkyl p-aminobenzoate, e.g., 2- (methylethylaminomethyl)cycloalkyl p- When any of the foregoing compounds are givento rats orally at a dose level of 3 mg/kg', increased motor activity is observed. One or more of the foregoing compounds may be administered to humans orally or by injection two or three times daily in doses of from 1 to 50 mg, preferably from about 5 to about mg. The administration of the foregoing compounds is especially suitable for geriatric use as the compounds are not anorectic agents.

The active compounds of the present invention may be utilized in compositions such as tablets, capsules, solutions or suspensions containing up to about 50 mg per unit of dosage of a compound or mixture of compounds of the present invention or a physiologically acceptable acid addition salt thereof. The compounds of the present invention may be compounded in conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer,

flavor, etc.', as called for by accepted pharmaceutical practice. I

The compounds of the present invention may be prepared by reacting a 2-dialkylaminomethylcycloal kanol with a p-nitrobenzoyl halide, followed by reduction of the nitro group to an amino group.

The desired 2-dialkylaminomethylcycloalkanols are obtained by condensing a cycloalkanone with paraldehyde or formaldehyde and a dialkylamine and reducing the dialkylaminomethylcycloalkanone to the corresponding dialkylaminomethylcycloalkanol.

In those cases where the desired final product is a monoalkylaminomethylcycloalkyl ester, the desired product is obtained by hydrogenolysis of the corresponding benzylalkylaminomethylcycloalkyl ester.

In those cases where v I 121 represents a heterocyclic ring, the desired products are obtained by condensing the heterocycle according to techniques known in the art. The cis or' trans form of the specific compounds may then be further resolved into individual enantiomorphs.

The compounds described herein form salts which are also part of this invention. The salts include acid ad dition salts, particularly the non-toxic.pharmaceutically acceptable salts. The salts may be formed by reacting the compounds of the present invention'with a variety of inorganic or organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate, toluenesulfonate and the like. The acid addition salts frequentlyv provide a convenient means for, isolating the product,

e.g., by forming the precipitating the salt in a medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of formula 1. Other salts may then be formed from the free base by reaction with an equivalent of acid.

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in degrees Centigrade.

, EXAMPLE 1 2-(Diethylaminomethyl)cyclohexyl p-aminobenzoate hydrochloride a. 2-( Diethylaminomethyl)cyclohexanone hydrochloride To a 2 liter flask is added 109 grams of diethylamine hydrochloride, 200 grams of cyclohexanone, 30 grams of paraformaldehyde and 400 ml of glacial acetic acid. The mixture is stirred and slowly heated to 60. The exothermic reaction that occurs is controlled by cooling the reaction mixture. The solution is heated at 7075 for 2.5 hours and then cooled and diluted with 2.5 liters of anhydrous ether. The product separates as an oil. The supernatant liquid is decanted and the residual oil triturated with 300 ml of anhydrous ether to give a semi-solid product, which is used without further purification in part b. Y

b. 2-(Diethylaminomethyl)cyclohexanol A solution of 43 grams of 2-(diethylaminomethyl) cyclohexanone (prepared in part a) in 200 ml of ethanol, to which is added 1 gram of platinum oxide, is shaken with hydrogen at 50 psi in a Parr hydrogenation apparatus. The hydrogen uptake ceases after about 2 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is dissolved in water and made strongly alkaline by the addition of sodium hydroxide pellets. The liberated base is extracted with ether and the ether dried over anhydrous magnesium sulfate. The solution is then concentrated and the residue fractionally distilled to yield the desired product, bp 88-90 at 2 to yield the crude product. After recrystallization from 200 ml of acetonitrile the product weighs 43 grams and melts at l84-l 86.

d. Z-(Diethylaminomethyl)cyclohexyl paminobenzoate hydrochloride To a warm solution of 20 grams of 2- (diethylaminomethyl)cyclohexyl p-nitrobenzoate hydrochloride in 250 ml of ethanol, there is added 3 grams of 5 percent palladium-on-carbon. The mixture is then hydrogenated at 50 psiof hydrogen in a Parr hydrogenation apparatus. The cooled mixture is filtered and concentrated under reduced pressure to remove the solvent. The oily residue is triturated with 500 ml of ether, yielding 35 grams of crude product, melting at l92l94. After crystallization from ethanol-ether and from acetonitrile the product melts at about l97-l98.

EXAMPLE 2 2-(Diethylaminomethyl)cyclopentyl p-aminobenzoate hydrochloride a. hydrochloride A mixture of 170 grams of cyclopentanone, 110 grams of diethylamine hydrochloride, 30 grams of paraformaldehyde and 400 ml of glacial acetic acid is stirred and heated slowly to The solution is maintained at 707 5 for 2.5 hours, cooled to room temperature and diluted with 2 liters of ether. The oily precipitate is tritur ated twice with ether and the semisolid product suspended in'a mixture of ethyl acetate and ether. The crude product is filtered, dried and washed with cold acetone to yield 147 grams of product melting at l l9l2l b. 2-(Diethylaminomethyl)cyclopentanol A suspension of 103 grams of 2- (diethylaminomethyl)-cyclopentanone hydrochloride in ml of water is layered with ether and treated with 75 grams of potassium carbonate in portions. The organic layer is separated and the slurry extracted with 50 ml portions of ether (3 times). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered, and the filtrate added portionwise to a stirred solution of 50 grams of sodium borohydride in 1 liter of methanol, while the temperature is maintained at 2030. The solution is stirred for 2 hours at room temperature and is then concentrated under reduced pressure. The residue, after removal of the solvent, is treated withml of water and the mixture extracted with ether. The dried ether solution is concentrated and the residue fractionated under reduced pressure to yieldthe desired 2-(diethylaminomethyl)cyclopentanol boiling at 76-78 at 2 mm.

c. 2-(Diethylaminomethyl)cyclopentyl nitrobenzoate hydrochloride Following the procedure of Example 10, but substituting an equivalent amount of (diethylaminomethyl)cyclopentanol for the 2- (diethylaminomethyl)cyclohexanol, there is obtained the desired Z-(diethylaminomethyl)cyclopentyl pnitrobenzoate hydrochloride, melting at l56-l58 after crystallization from isopropanol.

d. 2-(Diethylaminomethyl)cyclopentyl aminobenzoate hydrochloride Following the procedure of Example 1d, but sub- Z-(Diethylaminom ethyl)cyclopentanone stituting an equivalent amount of 2- (diethylaminomethyl)cyclopentyl p-nitrobenzoate hydrochloride for the Z-(diethylaminomethyl) EXAMPLE 3 2-( Dimethylaminomethyl )cycloheptyl aminobenzoate hydrochloride (diethylaminomethyl)cyclohexyl a. 2-(Dimethylaminomethyl)cycloheptanone A mixture of 112 grams of cycloheptanone, 75 grams of 40 percent aqueous formaldehyde and 81 grams of dimethylamine hydrochloride is stirred vigorously and heated to reflux in an atmosphere of carbon dioxide. Water and unreacted lcetone are removed by distillation under reduced pressure. The residue is dissolved in water and the free'base liberated by the addition of sodium carbonate. The mixture is extracted with ether and the ether dried over anhydrous potassium carbonate. After removal of the ether, the residue is purified by distillation under reduced pressure, boiling at 105 107 at-2.5 mm.

b. 2-(Dimethylaminomethyl)cycloheptyl aminobenzoate hydrochloride Following the procedure of Example 2, but substituting an equivalent amount of 2- (dimethylaminomethyl)cycloheptanone for the 2- (diethylaminomethyl)cyc1opentanone in part b), there is obtained the desired 2- (dimethylaminomethyl)cycloheptyl p-aminobenzoate hydrochloride.

EXAMPLE 4 2-'(Methylaminomethyl)cyclohexyl p-aminobenzoate hydrochloride a. 2-(Methylbenzylaminomethyl)cyclohexanone hydrochloride A mixture of 93 grams of cyclohexanone, 74.6 grams of methylbenzylamine hydrochloride and 14.3 grams of paraformaldehyde in 180 ml. of acetic acid is heated at 75 for 2.5 hours. The reaction is exothermic initially,

and cooling is necessary to maintain the temperature at 75. The reaction mixture is cooled, and 1.25 liters of ether is added with stirring. The oil, which separates, is dissolved in 400 ml. of acetone and 400 ml. of ether added. The product, which crystallizes upon cooling overnight, melts at 145-146.

b. 2-(Methylbenzylaminomethyl)cyclohexanol Following the procedure of Example 2b but substituting an equivalent amount benzylaminomethyl)cyclohexanone hydrochloride for the 2-(diethylaminomethyl)cyclopentanone hydrochloride, there is obtained the desired 2-(methylbenzyl-aminomethyl)cyclohexanol, boiling at l53-l5 4 at 2 mm.

c. 2-(Methylbenzylaminomethyl)cyclohexyl nitrobenzoate hydrochloride Following the procedure of Example 20, but substituting an equivalent amount of 2-(methylben zylaminomethyl)cyclohexanol for the 2- (diethylaminomethyl)cyclopentanol, there is obtained the desired 2-.(methylbenzylaminomethyl)cyclohexyl p-nitrobenzoate hydrochloride. The mixture of cis and trans melt at about l80l82. Fractional crystallization of this mixture of isomers yields a low melting isomer, melting at 183l85, and a high melting isomer, melting at 23 823 9.

d. 2-(Methylaminomethyl)cyclohexyl aminobenzoate hydrochloride Following the procedure of Example 1d but substituting an equivalent amount of 2- (benzylaminomethyl)cyclohexyl p-nitrobenzoate hydrochloride (m.p. 238239) for the 2- p-nitrobenzoate hydrochloride, there is obtained the desired 2- 6 (methylaminomethyl)cyclohexyl p-aminobenzoa'te hydrochloride, melting at about 163l65, after crystallization from acetonitrile.

EXAMPLE 5 times with ether. The aqueous solution is cooled,

layered with ether and made strongly alkaline by the addition, in portions, of about 200 grams of potassium carbonate. The ether layer is separated and the aqueous layer extracted several times with ether. The combined ether extracts are dried, filtered and concentrated to yield the desired 2-(l-piperidinylmethyl) cyclohexanone as an oil.

b. 2-( 1-Piperidinylmethyl)cyclohexanol To a stirred solution 'of 50 grams of sodium borohydride in 1.5 liters of methanol, there is added, dropwise, 180 grams of 2-( l-piperidinylmethy1)cyclohexan'one, maintaining the temperature at about 35 40 with cooling. The solution is refluxed for 1 hr. and is then concentrated to remove the sol-' vent. The'residue is treated with ml. of water and the mixture extracted several times with ether. The

combined ether extracts are dried, filtered and concentrated. The residue is fractionally distilled to yield the desired 2-(l-piperidinylmethyl)cyclohexanol, boiling at 107 at 2 mm.

c. 2-(1-Piperidinylmethyl)cyclohexyl nitrobenzoate hydrochloride Following the procedure of Example 10 but substituting an equivalent amount of 2-(1-piperidinylmethyl)cyclohexanol for the 2- (diethylaminomethyl)cyclohexanol, there is obtained the desired 2-(l-piperidinylmethyl)cyclohexyl pnitrobenzoate hydrochloride, melting at 191 219. The mixture of isomers is separated by fractional crystallization from dimethyl formamide to give two isomers, one melting at 249-250 (dec) and the more soluble isomer melting at about 194-196.

d. 2-(1-Piperidinylmethyl)cyclohexyl aminobenzoate hydrochloride Following the procedure of Example 1d but substituting an equivalent amount of Z-(l-piperidinylmethyl)cyclohexyl p-nitrobenzoate (m.p. 249 250) for the 2- (diethylaminomethyl)cyclohexyl p-nitroberizoate hydrochloride, there is obtained 2-(l-piperidinylmethyl)cyclohexyl p-aminobenzoate hydrochloride, melting at 220 222, after crystallization from acetonitrile. Following the procedure of Example 1d but substituting an equivalent amount of 2-(1- piperidinylmethyl)cyclohexanol p-nitrobenzoate hydrochloride (m.p. 194 196) for the 2 (diethylaminoethyl)-cyclohexyl p-nitrobenzoate hydrochloride EXAMPLE 6 2-( 1-Pyrrolidinylmethyl)cyclohexyl 'p-aminobenzoate hydrochloride a. 2-( 1-Pyrrolidinylmethy1)cyclohexanone Following the procedure 'of Example 5a, but substituting an equivalent amount of pyrrolidine for the piperidine, there is obtained the desired 2-(1-pyrrolidinylmethyl)cyclohexanone.

b. 2-( l-Pyrrolidinylmethyl)cyclohexanol Following the procedure of Example 5b, but substituting an equivalent amount of 2-(l-pyrrolidinylmethyl)cyclohexanone for the 2-(1-piperidinylmethyl)cyclohexanone, there is obtained the desired 2- (l-pyrrolidinylmethyl)cyclohexanol, boiling at 92 95 at 2 mm.

c. 2-( 1-Pyrrolidinylmethyl)cyclohexyl aminobenzoate hydrochloride Following the procedure of Example 1 but substituting an equivalent amount of 2-(l-pyrrolidinylmethyl)cyclohexanol for the 2- (diethylaminomethyl)cyclohexanol, there is obtained the desired 2-(l-pyrrolidinylmethy1)cyclohexyl paminobenzoate hydrochloride, melting at 188 190, after crystallization from acetonitrile.

EXAMPLE 7 2-(4-Morpholinylmethyl)cyclohexyl p-aminobenzoate hydrochloride a. 2-(4-Morpholinylmethyl)cyclohexanone hydrochloride Following the procedure of Example 1a, but substituting an equivalent amount of morpholine hydrochloride for the diethylamine hydrochloride, there is obtained the desired 2-(4-morpholinylmethyl)cyclohexanone hydrochloride, melting at 144 146.

b. 2-(4-Morpholinylmethyl)cyclohexanol Following the procedure of Example 212, but substituting an equivalent. amount of 2-(4-morpholinylmethyl)cyclohexanone hydrochloride for the 2- (diethylaminomethyl)cyclopentanone hydrochloride, there is obtained the desired 2-(4-morpholinyl)cyclohexanol, boiling at 120 122 at 2 mm.

c. 2-(4-Morpholinylmethyl)cyclohexyl nitrobenzoate hydrochloride Following the procedure of Example 1c, but substituting an equivalent amount of 2-(4-morpholinylmethyl)cyclohexanol for the 2- (diethylaminomethyl)cyclohexanol, there is obtained the desired 2-(4-morpholinylmethyl)cyclohexyl pnitrobenzoate hydrochloride, melting at about 191 202. This mixture of isomers is separated by fractional crystallization from acetonitrile to yield two isomers, one melting at 248 250 (dec) and the second isomer melting at 199- 201 (dec.)

d. 2-(4-Morpholinylmethyl)cyclohexyl aminobenzoate hydrochloride Following the procedure of Example 1d, but substituting an equivalent amount of 2-(4-morpholinylmethyl)cyclohexyl p-nitrobenzoate hydrochloride (mp. 248 250) for the 2- (diethylaminomethyl)cyclohexyl p-nitrobenzoate hydrochloride, there is obtained the 2-(4-morpholinylmethyl)'cyc1ohexyl p-aminobenzoate hydrochloride melting at 181 183 after crystallization from acetonitrile.

Similarly, by using an equivalent amount of 2-(4- morpholinylrnethyl)cyclohexyl p-nitrobenzoate hydrochloride (mp. 199 201), there is obtained the 2-(4-morpholinylmethyl)-cyclohexyl p-aminobenzoate hydrochloride, melting at 215 217 after crystallization from acetonitrile.

EXAMPLE 8 Parenteral Formulation A sterile powder for reconstitution for parenteral use is prepared from the following ingredients:

Z-(Diethylaminoethyl)cyclohexyl p-aminobenzoate hydrochloride mg. Benzyl alcohol mg. Sodium chloride 35 mg.

The sterile powder is aseptically blended and filled into ten sterile vials, each containing 28.5 mg., and sealed. The addition of 1 m1. of water for injection to the vial provides a solution of intramuscularinjection.

EXAMPLE 9 2-( Diethylaminoethyl)cyclohexyl p-aminobenzoate hydrochloride 150 mg. Benzyl alcohol 150 mg. Sodium chloride 30 mg. Water for injection q.s. to 10 ml.

The solution of the foregoing ingredients is filled into ten sterile vials, each containing 1 ml., sealed and stored under refrigeration.

EXAMPLE 10 Oral Tablet The following ingredients are thoroughly mixed in a Hobart blender:

2-( Diethylaminoethyl )cyclohexyl p-aminobenzoate hydrochloride 1,000 mg. Corn starch 1,125 mg. Lactose 8,000 mg. Magnesium stearate 100 mg. Avicel (microcrystalline cellulose) 2,250 mg.

The blended mixture is then compressed into tablets in normal manner to make 100 tablets.

What is claimed is:

l. A method of stimulating the central nervous system comprising administering to humans an effective amount ofa compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein n isO, l or 2 R is hydrogen or lower alkyl of up to 4 carbon atoms, R is lower alkyl of up to four carbon atoms, and R and R, together with the nitrogen atom to which they are bonded are piperidino, morpholino or pyrrolidino.

2. A method of stimulating the central nervous system comprising administering an effective amount of a compound of claim 1 in combination with a pharm aceutically acceptable carrier.

3. vA method according to claim 1 wherein the about 50 mg.

amount of compound administered is about-l mg. to

Po-ww UNITED STATES PATENTWOFFICE 5 6 CER'HFICATE OF CURRECTION Patent 37O8'586 Dated January 2, 1973 Invantofla Pier??? Simon et It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4,' line 37, "20 -30" should read 2o-30--.

Cblumn 7, line 2, "peaminobenzoate" should read p-aminobenzoate.

Celumri 7, line 50, "nyl) should read nylmethyl).

Signed "arid sealed this 5th day of March 197A.

(SEAL) Attest: v I EDWARD MQFLE TCHERJR. C. M1RSHA L DANN Attesting Offi Commlssloner of Patents 

2. A method of stimulating the central nervous system comprising administering an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
 3. A method according to claim 1 wherein the amount of compound administered is about 1 mg. to about 50 mg.
 4. A method according to claim 3 wherein the amount administered is from about 5 mg. to about 20 mg.
 5. A method according to claim 1 wherein R and R1 are each alkyl and wherein the number of carbon atoms in R and R1 is at least
 3. 6. A method according to claim 5 wherein R and R1 are each ethyl.
 7. A method according to claim 6 wherein n is
 1. 